BACTRIM DS- sulfamethoxazole and trimethoprim tablet BACTRIM- sulfamethoxazole and trimethoprim tablet Sun Pharmaceutical Industries, Inc----------BACTRIM™ sulfamethoxazole and trimethoprim DS (double strength) tablets and tablets USPRx onlyTo reduce the development of drug-resistant bacteria and maintain the effectiveness ofBactrim (sulfamethoxazole and trimethoprim) tablets and other antibacterial drugs,Bactrim (sulfamethoxazole and trimethoprim) tablets should be used only to treat orprevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTIONBACTRIM (sulfamethoxazole and trimethoprim) is a synthetic antibacterial combinationproduct available in DS (double strength) tablets, each containing 800 mgsulfamethoxazole and 160 mg trimethoprim; in tablets, each containing 400 mgsulfamethoxazole and 80 mg trimethoprim for oral administration.Sulfamethoxazole is N -(5-methyl-3-isoxazolyl) sulfanilamide; the molecular formula isC H N O S. It is an almost white, odorless, tasteless compound with a molecularweight of 253.28 and the following structural formula:

Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine; the molecularformula is C H N O . It is a white to light yellow, odorless, bitter compound with amolecular weight of 290.3 and the following structural formula:

1

10 11 3 3

14 18 4 3

Inactive ingredients: Docusate sodium 85%, sodium benzoate 15%, sodium starchglycolate, magnesium stearate and pregelatinized starch.

CLINICAL PHARMACOLOGYBACTRIM is rapidly absorbed following oral administration. Both sulfamethoxazole andtrimethoprim exist in the blood as unbound, protein-bound and metabolized forms;sulfamethoxazole also exists as the conjugated form. Sulfamethoxazole is metabolizedin humans to at least 5 metabolites: the N -acetyl-, N -hydroxy-, 5-methylhydroxy-, N -acetyl-5-methylhydroxy- sulfamethoxazole metabolites, and an N-glucuronide conjugate.The formulation of N -hydroxy metabolite is mediated via CYP2C9.Trimethoprim is metabolized in vitro to 11 different metabolites, of which, five areglutathione adducts and six are oxidative metabolites, including the major metabolites, 1-and 3-oxides and the 3- and 4-hydroxy derivatives.The free forms of sulfamethoxazole and trimethoprim are considered to be thetherapeutically active forms.In vitro studies suggest that trimethoprim is a substrate of P-glycoprotein, OCT1 andOCT2, and that sulfamethoxazole is not a substrate of P-glycoprotein.Approximately 70% of sulfamethoxazole and 44% of trimethoprim are bound to plasmaproteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases theprotein binding of trimethoprim by an insignificant degree; trimethoprim does notinfluence the protein binding of sulfamethoxazole.Peak blood levels for the individual components occur 1 to 4 hours after oraladministration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10and 8 to 10 hours, respectively. However, patients with severely impaired renal functionexhibit an increase in the half-lives of both components, requiring dosage regimenadjustment (see DOSAGE AND ADMINISTRATION section). Detectable amounts ofsulfamethoxazole and trimethoprim are present in the blood 24 hours after drugadministration. During administration of 800 mg sulfamethoxazole and 160 mgtrimethoprim b.i.d., the mean steady-state plasma concentration of trimethoprim was1.72 µg/mL. The steady-state mean plasma levels of free and total sulfamethoxazolewere 57.4 µg/mL and 68.0 µg/mL, respectively. These steady-state levels were achievedafter three days of drug administration. Excretion of sulfamethoxazole andtrimethoprim is primarily by the kidneys through both glomerular filtration and tubularsecretion. Urine concentrations of both sulfamethoxazole and trimethoprim areconsiderably higher than are the concentrations in the blood. The average percentage ofthe dose recovered in urine from 0 to 72 hours after a single oral dose ofsulfamethoxazole and trimethoprim is 84.5% for total sulfonamide and 66.8% for freetrimethoprim. Thirty percent of the total sulfonamide is excreted as freesulfamethoxazole, with the remaining as N -acetylated metabolite. When administeredtogether as sulfamethoxazole and trimethoprim, neither sulfamethoxazole nortrimethoprim affects the urinary excretion pattern of the other.Both sulfamethoxazole and trimethoprim distribute to sputum, vaginal fluid and middleear fluid; trimethoprim also distributes to bronchial secretion, and both pass theplacental barrier and are excreted in human milk.Pharmacokinetics in Pediatric Patients

4 4 4

4

1

4 2

A simulation conducted with data from a pharmacokinetic study in 153 infants andchildren demonstrated that mean steady state AUC and maximum plasma concentrationof trimethoprim and sulfamethoxazole would be comparable between pediatric patients2 months to 18 years receiving 8/40 (trimethoprim/ sulfamethoxazole) mg/kg/daydivided every 12 hours and adult patients receiving 320/1600 (trimethoprim/sulfamethoxazole) mg/day.Pharmacokinetics in Geriatric PatientsThe pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg werestudied in 6 geriatric subjects (mean age: 78.6 years) and 6 young healthy subjects(mean age: 29.3 years) using a non-US approved formulation. Pharmacokinetic valuesfor sulfamethoxazole in geriatric subjects were similar to those observed in young adultsubjects. The mean renal clearance of trimethoprim was significantly lower in geriatricsubjects compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg). However,after normalizing by body weight, the apparent total body clearance of trimethoprim wason average 19% lower in geriatric subjects compared with young adult subjects.

MicrobiologyMechanism of ActionSulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing withpara-aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolicacid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme,dihydrofolate reductase. Thus, sulfamethoxazole and trimethoprim blocks twoconsecutive steps in the biosynthesis of nucleic acids and proteins essential to manybacteria.ResistanceIn vitro studies have shown that bacterial resistance develops more slowly with bothsulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole ortrimethoprim alone.Antimicrobial ActivityBACTRIM has been shown to be active against most isolates of the followingmicroorganisms, both in vitro and in clinical infections as described in the INDICATIONSAND USAGEsection.Aerobic gram-positive bacteriaStreptococcus pneumoniae

Aerobic gram-negative bacteriaEscherichia coli (including susceptible enterotoxigenic strains implicated in traveler'sdiarrhea)Klebsiella speciesEnterobacter speciesHaemophilus influenzae

Morganella morganii

3

Proteus mirabilis

Proteus vulgaris

Shigella flexneri

Shigella sonnei

Other MicroorganismsPneumocystis jirovecii

Susceptibility TestingFor specific information regarding susceptibility test interpretive criteria and associatedtest methods and quality control standards recognized by FDA for this drug, please see:https://www.fda.gov/STIC.

INDICATIONS AND USAGETo reduce the development of drug-resistant bacteria and maintain the effectiveness ofBactrim (sulfamethoxazole and trimethoprim) tablets and other antibacterial drugs,Bactrim (sulfamethoxazole and trimethoprim) tablets should be used only to treat orprevent infections that are proven or strongly suspected to be caused by susceptiblebacteria. When culture and susceptibility information are available, they should beconsidered in selecting or modifying antibacterial therapy. In the absence of such data,local epidemiology and susceptibility patterns may contribute to empiric selection oftherapy.Urinary Tract InfectionsFor the treatment of urinary tract infections due to susceptible strains of the followingorganisms: Escherichia coli, Klebsiella species, Enterobacter species, Morganellamorganii, Proteus mirabilis and Proteus vulgaris. It is recommended that initial episodesof uncomplicated urinary tract infections be treated with a single effective antibacterialagent rather than the combination.Acute Otitis MediaFor the treatment of acute otitis media in pediatric patients due to susceptible strains ofStreptococcus pneumoniae or Haemophilus influenzae when in the judgment of thephysician sulfamethoxazole and trimethoprim offers some advantage over the use ofother antimicrobial agents. To date, there are limited data on the safety of repeated useof BACTRIM in pediatric patients under two years of age. BACTRIM is not indicated forprophylactic or prolonged administration in otitis media at any age.Acute Exacerbations of Chronic Bronchitis in AdultsFor the treatment of acute exacerbations of chronic bronchitis due to susceptiblestrains of Streptococcus pneumoniae or Haemophilus influenzae when a physiciandeems that BACTRIM could offer some advantage over the use of a single antimicrobialagent.ShigellosisFor the treatment of enteritis caused by susceptible strains of Shigella flexneri andShigella sonnei when antibacterial therapy is indicated.

Pneumocystis jirovecii PneumoniaFor the treatment of documented Pneumocystis jirovecii pneumonia and for prophylaxisagainst P. jirovecii pneumonia in individuals who are immunosuppressed and consideredto be at an increased risk of developing P. jirovecii pneumonia.Traveler's Diarrhea in AdultsFor the treatment of traveler's diarrhea due to susceptible strains of enterotoxigenic E.coli.

CONTRAINDICATIONSBACTRIM is contraindicated in the following situations:

••

•••••

WARNINGS

Hypersensitivity and Other Serious or Fatal ReactionsFatalities and serious adverse reactions including severe cutaneous adverse reactions(SCARs) including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reactionwith eosinophilia and systemic symptoms (DRESS), acute febrile neutrophilic dermatosis(AFND), acute generalized erythematous pustulosis (AGEP); fulminant hepatic necrosis;agranulocytosis, aplastic anemia and other blood dyscrasias; acute and delayed lunginjury; anaphylaxis and circulatory shock have occurred with the administration ofsulfamethoxazole and trimethoprim products, including BACTRIM (see ADVERSEREACTIONS).Cough, shortness of breath and pulmonary infiltrates potentially representinghypersensitivity reactions of the respiratory tract have been reported in association withsulfamethoxazole and trimethoprim treatment.Other severe pulmonary adverse reactions occurring within days to week of BACTRIMinitiation and resulting in prolonged respiratory failure requiring mechanical ventilation orextracorporeal membrane oxygenation (ECMO), lung transplantation or death have alsobeen reported in patients and otherwise healthy individuals treated withsulfamethoxazole and trimethoprim products.Circulatory shock with fever, severe hypotension, and confusion requiring intravenousfluid resuscitation and vasopressors has occurred within minutes to hours of re-challenge with sulfamethoxazole and trimethoprim products, including BACTRIM, inpatients with history of recent (days to weeks) exposure to sulfamethoxazole andtrimethoprim.

a known hypersensitivity to trimethoprim or sulfonamideshistory of drug-induced immune thrombocytopenia with use of trimethoprim and/orsulfonamidesdocumented megaloblastic anemia due to folate deficiencypediatric patients less than 2 months of agemarked hepatic damagesevere renal insufficiency when renal function status cannot be monitoredconcomitant administration with dofetilide (see PRECAUTIONS).

BACTRIM should be discontinued at the first appearance of skin rash or any sign of aserious adverse reaction. A skin rash may be followed by a more severe reaction, suchas Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, AFND, AGEP, hepaticnecrosis, or serious blood disorders (see PRECAUTIONS and ADVERSEREACTIONS). Clinical signs, such as rash, pharyngitis, fever, arthralgia, cough, chestpain, dyspnea, pallor, purpura or jaundice may be early indications of serious reactions.

ThrombocytopeniaBACTRIM-induced thrombocytopenia may be an immune-mediated disorder. Severecases of thrombocytopenia that are fatal or life threatening have been reported.Thrombocytopenia usually resolves within a week upon discontinuation of BACTRIM.

Streptococcal Infections and Rheumatic FeverThe sulfonamides should not be used for treatment of group A β-hemolyticstreptococcal infections. In an established infection, they will not eradicate thestreptococcus and, therefore, will not prevent sequelae such as rheumatic fever.

Clostridioides difficile Associated DiarrheaClostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly allantibacterial agents, including BACTRIM, and may range in severity from mild diarrhea tofatal colitis. Treatment with antibacterial agents alters the normal flora of the colonleading to overgrowth of C. difficile.C. difficile produces toxins A and B which contribute to the development of CDAD.Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, asthese infections can be refractory to antimicrobial therapy and may require colectomy.CDAD must be considered in all patients who present with diarrhea following antibioticuse. Careful medical history is necessary since CDAD has been reported to occur overtwo months after the administration of antibacterial agents.If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficilemay need to be discontinued. Appropriate fluid and electrolyte management, proteinsupplementation, antibiotic treatment of C. difficile, and surgical evaluation should beinstituted as clinically indicated.

Risk Associated with Concurrent Use of Leucovorin for Pneumocystisjirovecii PneumoniaTreatment failure and excess mortality were observed when BACTRIM was usedconcomitantly with leucovorin for the treatment of HIV positive patients with P. jiroveciipneumonia in a randomized placebo-controlled trial. Avoid coadministration of BACTRIMand leucovorin during treatment of P. jirovecii pneumonia.

PRECAUTIONSDevelopment of Drug Resistant BacteriaPrescribing Bactrim (sulfamethoxazole and trimethoprim) tablets in the absence of aproven or strongly suspected bacterial infection or a prophylactic indication is unlikely toprovide benefit to the patient and increases the risk of the development of drug-

4

resistant bacteria.Folate DeficiencyAvoid use of BACTRIM in patients with impaired renal or hepatic function, in those withpossible folate deficiency (e.g., the elderly, chronic alcoholics, patients receivinganticonvulsant therapy, patients with malabsorption syndrome, and patients inmalnutrition states) and in those with severe allergies or bronchial asthma.Hematological changes indicative of folic acid deficiency may occur in elderly patients orin patients with preexisting folic acid deficiency or kidney failure. These effects arereversible by folinic acid therapy (see PRECAUTIONS, Geriatric Use).HemolysisIn glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. Thisreaction is frequently dose-related.HypoglycemiaCases of hypoglycemia in non-diabetic patients treated with BACTRIM are seen rarely,usually occurring after a few days of therapy. Patients with renal dysfunction, liverdisease, malnutrition or those receiving high doses of BACTRIM are particularly at risk.Impaired Phenylalanine MetabolismThe trimethoprim component of BACTRIM has been noted to impair phenylalaninemetabolism, but this is of no significance in phenylketonuric patients on appropriatedietary restriction.Porphyria and HypothyroidismLike other drugs containing sulfonamides, BACTRIM can precipitate porphyria crisis andhypothyroidism. Avoid use of BACTRIM in patients with porphyria or thyroid dysfunction.

Potential Risk in the Treatment of Pneumocystis jirovecii Pneumonia inPatients with Acquired Immunodeficiency Syndrome (AIDS)AIDS patients may not tolerate or respond to BACTRIM in the same manner as non-AIDSpatients. The incidence of adverse reactions, particularly rash, fever, leukopenia andelevated aminotransferase (transaminase) values, with BACTRIM therapy in AIDSpatients who are being treated for P. jirovecii pneumonia has been reported to beincreased compared with the incidence normally associated with the use of BACTRIM innon-AIDS patients. If a patient develops skin rash, fever, leukopenia or any sign ofadverse reaction, reevaluate benefit-risk of continuing therapy or re-challenge withBACTRIM (see WARNINGS).Avoid coadministration of BACTRIM and leucovorin during treatment of P. jiroveciipneumonia (see WARNINGS).Electrolyte AbnormalitiesHyperkalemia: High dosage of trimethoprim, as used in patients with P. jiroveciipneumonia, induces a progressive but reversible increase of serum potassiumconcentrations in a substantial number of patients. Even treatment with recommendeddoses may cause hyperkalemia when trimethoprim is administered to patients withunderlying disorders of potassium metabolism, with renal insufficiency, or if drugs

known to induce hyperkalemia are given concomitantly. Close monitoring of serumpotassium is warranted in these patients.Hyponatremia: Severe and symptomatic hyponatremia can occur in patients receivingBACTRIM, particularly for the treatment of P. jirovecii pneumonia. Evaluation forhyponatremia and appropriate correction is necessary in symptomatic patients toprevent life-threatening complications.Crystalluria: During treatment, ensure adequate fluid intake and urinary output toprevent crystalluria. Patients who are “slow acetylators” may be more prone toidiosyncratic reactions to sulfonamides.

Information for PatientsPatients should be counseled that antibacterial drugs including Bactrim(sulfamethoxazole and trimethoprim) tablets should only be used to treat bacterialinfections. They do not treat viral infections (e.g., the common cold). When Bactrim(sulfamethoxazole and trimethoprim) tablets are prescribed to treat a bacterial infection,patients should be told that although it is common to feel better early in the course oftherapy, the medication should be taken exactly as directed. Skipping doses or notcompleting the full course of therapy may (1) decrease the effectiveness of theimmediate treatment and (2) increase the likelihood that bacteria will develop resistanceand will not be treatable by Bactrim (sulfamethoxazole and trimethoprim) tablets orother antibacterial drugs in the future.Patients should be instructed to maintain an adequate fluid intake in order to preventcrystalluria and stone formation.Diarrhea is a common problem caused by antibiotics which usually ends when theantibiotic is discontinued. Sometimes after starting treatment with antibiotics, patientscan develop watery and bloody stools (with or without stomach cramps and fever) evenas late as two or more months after having taken the last dose of the antibiotic. If thisoccurs, patients should contact their physician as soon as possible.

Laboratory TestsComplete blood counts and clinical chemistry testing should be done frequently inpatients receiving BACTRIM. Perform urinalyses with careful microscopic examinationand renal function tests during therapy, particularly for those patients with impairedrenal function. Discontinue BACTRIM if a significant electrolyte abnormality, renalinsufficiency or reduction in the count of any formed blood element is noted.

Drug InteractionsPotential for BACTRIM to Affect Other Drugs

Trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole isan inhibitor of CYP2C9. Avoid coadministration of BACTRIM with drugs that aresubstrates of CYP2C8 and 2C9 or OCT2.Table 1: Drug Interactions with BACTRIM

Drug(s) Recommendation CommentsDiuretics Avoid concurrent use In elderly patients concurrently receiving

certain diuretics, primarily thiazides, anincreased incidence of thrombocytopeniawith purpura has been reported.

Warfarin Monitor prothrombintime

and INR

It has been reported that BACTRIM mayprolong the prothrombin time in patientswho are receiving the anticoagulantwarfarin (a CYP2C9 substrate). Thisinteraction should be kept in mind whenBACTRIM is given to patients already onanticoagulant therapy, and the coagulationtime should be reassessed.

Phenytoin Monitor serumphenytoin levels

BACTRIM may inhibit the hepaticmetabolism of phenytoin (a CYP2C9substrate). BACTRIM, given at a commonclinical dosage, increased the phenytoinhalf-life by 39% and decreased thephenytoin metabolic clearance rate by 27%.When administering these drugsconcurrently, one should be alert forpossible excessive phenytoin effect.

Methotrexate Avoid concurrent use Sulfonamides can also displacemethotrexate from plasma protein bindingsites and can compete with the renaltransport of methotrexate, thus increasingfree methotrexate concentrations.

Cyclosporine Avoid concurrent use There have been reports of marked butreversible nephrotoxicity withcoadministration of BACTRIM andcyclosporine in renal transplant recipients.

Digoxin Monitor serum digoxinlevels

Increased digoxin blood levels can occurwith concomitant BACTRIM therapy,especially in elderly patients.

Indomethacin Avoid concurrent use Increased sulfamethoxazole blood levelsmay occur in patients who are alsoreceiving indomethacin.

Pyrimethamine Avoid concurrent use Occasional reports suggest that patientsreceiving pyrimethamine as malariaprophylaxis in doses exceeding 25 mgweekly may develop megaloblastic anemia ifBACTRIM is prescribed.

TricyclicAntidepressants(TCAs)

Monitor therapeuticresponse and adjust

dose of TCA accordingly

The efficacy of tricyclic antidepressants candecrease when coadministered withBACTRIM.

OralHypoglycemics

Monitor blood glucosemore frequently

Like other sulfonamide-containing drugs,BACTRIM potentiates the effect of oralhypoglycemic that are metabolized byCYP2C8 (e.g., pioglitazone, repaglinide, androsiglitazone) or CYP2C9 (e.g., glipizide andglyburide) or eliminated renally via OCT2

(e.g., metformin). Additional monitoring ofblood glucose may be warranted.

Amantadine Avoid concurrent use In the literature, a single case of toxicdelirium has been reported afterconcomitant intake of BACTRIM andamantadine (an OCT2 substrate). Cases ofinteractions with other OCT2 substrates,memantine and metformin, have also beenreported.

AngiotensinConvertingEnzymeInhibitors

Avoid concurrent use In the literature, three cases ofhyperkalemia in elderly patients have beenreported after concomitant intake ofBACTRIM and an angiotensin convertingenzyme inhibitor.

Zidovudine Monitor for hematologictoxicity

Zidovudine and BACTRIM are known toinduce hematological abnormalities. Hence,there is potential for an additivemyelotoxicity when coadministered.

Dofetilide Concurrentadministration iscontraindicated

Elevated plasma concentrations of dofetilidehave been reported following concurrentadministration of trimethoprim anddofetilide. Increased plasma concentrationsof dofetilide may cause serious ventriculararrhythmias associated with QT intervalprolongation, including torsade depointes.

Procainamide Closely monitor forclinical and ECG signs of

procainamide toxicityand/or procainamide

plasma concentration ifavailable

Trimethoprim increases the plasmaconcentrations of procainamide and itsactive N-acetyl metabolite (NAPA) whentrimethoprim and procainamide arecoadministered. The increasedprocainamide and NAPA plasmaconcentrations that resulted from thepharmacokinetic interaction withtrimethoprim are associated with furtherprolongation of the QTc interval.

Drug/Laboratory Test InteractionsBACTRIM, specifically the trimethoprim component, can interfere with a serummethotrexate assay as determined by the competitive binding protein technique (CBPA)when a bacterial dihydrofolate reductase is used as the binding protein. No interferenceoccurs, however, if methotrexate is measured by a radioimmunoassay (RIA).The presence of BACTRIM may also interfere with the Jaffé alkaline picrate reaction assayfor creatinine, resulting in overestimations of about 10% in the range of normal values.

Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis

5,6

7

8,9

10

Sulfamethoxazole was not carcinogenic when assessed in a 26-week tumorigenic mouse(Tg-rasH2) study at doses up to 400 mg/kg/day sulfamethoxazole; equivalent to 2.4-foldthe human systemic exposure (at a daily dose of 800 mg sulfamethoxazole twice a day).Mutagenesis

In vitro reverse mutation bacterial tests according to the standard protocol have notbeen performed with sulfamethoxazole and trimethoprim in combination. An in vitrochromosomal aberration test in human lymphocytes with sulfamethoxazole andtrimethoprim was negative. In in vitro and in vivo tests in animal species,sulfamethoxazole and trimethoprim did not damage chromosomes. In vivo micronucleusassays were positive following oral administration of sulfamethoxazole and trimethoprim.Observations of leukocytes obtained from patients treated with sulfamethoxazole andtrimethoprim revealed no chromosomal abnormalities.Sulfamethoxazole alone was positive in an in vitro reverse mutation bacterial assay andin in vitro micronucleus assays using cultured human lymphocytes.Trimethoprim alone was negative in in vitro reverse mutation bacterial assays and in invitro chromosomal aberration assays with Chinese Hamster ovary or lung cells with orwithout S9 activation. In in vitro Comet, micronucleus and chromosomal damage assaysusing cultured human lymphocytes, trimethoprim was positive. In mice following oraladministration of trimethoprim, no DNA damage in Comet assays of liver, kidney, lung,spleen, or bone marrow was recorded.Impairment of Fertility

No adverse effects on fertility or general reproductive performance were observed inrats given oral dosages as high as 350 mg/kg/day sulfamethoxazole plus 70 mg/kg/daytrimethoprim, doses roughly two times the recommended human daily dose on a bodysurface area basis.

PregnancyWhile there are no large, well-controlled studies on the use of sulfamethoxazole andtrimethoprim in pregnant women, Brumfitt and Pursell, in a retrospective study,reported the outcome of 186 pregnancies during which the mother received eitherplacebo or sulfamethoxazole and trimethoprim. The incidence of congenitalabnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) inthose receiving sulfamethoxazole and trimethoprim. There were no abnormalities in the10 children whose mothers received the drug during the first trimester. In a separatesurvey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whosemothers had received oral sulfamethoxazole and trimethoprim at the time of conceptionor shortly thereafter.Because sulfamethoxazole and trimethoprim may interfere with folic acid metabolism,BACTRIM should be used during pregnancy only if the potential benefit justifies thepotential risk to the fetus.

Teratogenic EffectsHuman Data

While there are no large prospective, well controlled studies in pregnant women andtheir babies, some retrospective epidemiologic studies suggest an association between

11

first trimester exposure to sulfamethoxazole and trimethoprim with an increased risk ofcongenital malformations, particularly neural tube defects, cardiovascular abnormalities,urinary tract defects, oral clefts, and club foot. These studies, however, were limited bythe small number of exposed cases and the lack of adjustment for multiple statisticalcomparisons and confounders. These studies are further limited by recall, selection, andinformation biases, and by limited generalizability of their findings. Lastly, outcomemeasures varied between studies, limiting cross-study comparisons. Alternatively, otherepidemiologic studies did not detect statistically significant associations betweensulfamethoxazole and trimethoprim exposure and specific malformations.Animal Data

In rats, oral doses of either 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprimproduced teratologic effects manifested mainly as cleft palates. These doses areapproximately 5 and 6 times the recommended human total daily dose on a bodysurface area basis. In two studies in rats, no teratology was observed when 512 mg/kgof sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In somerabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) wasassociated with doses of trimethoprim 6 times the human therapeutic dose based onbody surface area.

Nonteratogenic EffectsSee CONTRAINDICATIONS section.

Nursing MothersLevels of sulfamethoxazole and trimethoprim in breast milk are approximately 2–5% ofthe recommended daily dose for infants over 2 months of age. Caution should beexercised when BACTRIM is administered to a nursing woman, especially whenbreastfeeding jaundiced, ill, stressed, or premature infants because of the potential riskof bilirubin displacement and kernicterus.

Pediatric UseBACTRIM is contraindicated for infants younger than 2 months of age (seeINDICATIONS AND USAGE and CONTRAINDICATIONS sections).

Geriatric UseClinical studies of BACTRIM did not include sufficient numbers of subjects aged 65 andover to determine whether they respond differently from younger subjects.There may be an increased risk of severe adverse reactions in elderly patients,particularly when complicating conditions exist, e.g., impaired kidney and/or liverfunction, possible folate deficiency, or concomitant use of other drugs. Severe skinreactions, generalized bone marrow suppression (see WARNINGS and ADVERSEREACTIONS sections), a specific decrease in platelets (with or without purpura), andhyperkalemia are the most frequently reported severe adverse reactions in elderlypatients. In those concurrently receiving certain diuretics, primarily thiazides, anincreased incidence of thrombocytopenia with purpura has been reported. Increaseddigoxin blood levels can occur with concomitant BACTRIM therapy, especially in elderlypatients. Serum digoxin levels should be monitored. Hematological changes indicative of

folic acid deficiency may occur in elderly patients. These effects are reversible by folinicacid therapy. Appropriate dosage adjustments should be made for patients withimpaired kidney function and duration of use should be as short as possible to minimizerisks of undesired reactions (see DOSAGE AND ADMINISTRATION section). Thetrimethoprim component of BACTRIM may cause hyperkalemia when administered topatients with underlying disorders of potassium metabolism, with renal insufficiency orwhen given concomitantly with drugs known to induce hyperkalemia, such asangiotensin converting enzyme inhibitors. Close monitoring of serum potassium iswarranted in these patients. Discontinuation of BACTRIM treatment is recommended tohelp lower potassium serum levels. Bactrim Tablets contain 1.8 mg sodium (0.08 mEq)of sodium per tablet. Bactrim DS Tablets contain 3.6 mg (0.16 mEq) of sodium pertablet.Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjectsand younger adult subjects. The mean maximum serum trimethoprim concentration washigher and mean renal clearance of trimethoprim was lower in geriatric subjectscompared with younger subjects (see CLINICAL PHARMACOLOGY: GeriatricPharmacokinetics).

ADVERSE REACTIONSThe following adverse reactions associated with the use of BACTRIM orsulfamethoxazole and trimethoprim were identified in clinical trials, postmarketing orpublished reports. Because some of these reactions were reported voluntarily from apopulation of uncertain size, it is not always possible to reliably estimate their frequencyor establish a causal relationship to drug exposure.The most common adverse reactions are gastrointestinal disturbances (nausea,vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). Fatalitiesand serious adverse reactions, including severe cutaneous adverse reactions(SCARs), including Stevens-Johnson syndrome, toxic epidermal necrolysis,drug reaction with eosinophilia and systemic symptoms (DRESS), acutefebrile neutrophilic dermatosis (AFND), acute generalized erythematouspustulosis (AGEP); fulminant hepatic necrosis; agranulocytosis, aplasticanemia and other blood dyscrasias; acute and delayed lung injury;anaphylaxis and circulatory shock have occurred with the administration ofsulfamethoxazole and trimethoprim products, including BACTRIM(seeWARNINGS).Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia,neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia,methemoglobinemia, eosinophilia, thrombotic thrombocytopenic purpura, idiopathicthrombocytopenic purpura.Allergic Reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis,allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever,chills, Henoch-Schoenlein purpura, serum sickness-like syndrome, generalized allergicreactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection,pruritus, urticaria, rash, periarteritis nodosa, systemic lupus erythematosus, drugreaction with eosinophilia and systemic symptoms (DRESS), acute generalizederythematous pustulosis (AGEP), and acute febrile neutrophilic dermatosis (AFND) (seeWARNINGS).

WARNINGS).Gastrointestinal: Hepatitis (including cholestatic jaundice and hepatic necrosis), elevationof serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis,stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia.Genitourinary: Renal failure, interstitial nephritis, BUN and serum creatinine elevation,renal insufficiency, oliguria and anuria, crystalluria and nephrotoxicity in association withcyclosporine.Metabolic and Nutritional: Hyperkalemia, hyponatremia (see PRECAUTIONS:Electrolyte Abnormalities), metabolic acidosis.Neurologic: Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus,headache.Psychiatric: Hallucinations, depression, apathy, nervousness.Endocrine: The sulfonamides bear certain chemical similarities to some goitrogens,diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have occurred.Musculoskeletal: Arthralgia, myalgia, rhabdomyolysis.Respiratory: Cough, shortness of breath and pulmonary infiltrates, acute eosinophilicpneumonia, acute and delayed lung injury, interstitial lung disease, acute respiratoryfailure (see WARNINGS).Cardiovascular System: QT prolongation resulting in ventricular tachycardia and torsadesde pointes, circulatory shock (seeWARNINGS).Miscellaneous: Weakness, fatigue, insomnia.

OVERDOSAGEAcuteThe amount of a single dose of BACTRIM that is either associated with symptoms ofoverdosage or is likely to be life-threatening has not been reported. Signs andsymptoms of overdosage reported with sulfonamides include anorexia, colic, nausea,vomiting, dizziness, headache, drowsiness and unconsciousness. Pyrexia, hematuriaand crystalluria may be noted. Blood dyscrasias and jaundice are potential latemanifestations of overdosage.Signs of acute overdosage with trimethoprim include nausea, vomiting, dizziness,headache, mental depression, confusion and bone marrow depression.General principles of treatment include the institution of gastric lavage or emesis, forcingoral fluids, and the administration of intravenous fluids if urine output is low and renalfunction is normal. Acidification of the urine will increase renal elimination oftrimethoprim. The patient should be monitored with blood counts and appropriate bloodchemistries, including electrolytes. If a significant blood dyscrasia or jaundice occurs,specific therapy should be instituted for these complications. Peritoneal dialysis is noteffective and hemodialysis is only moderately effective in eliminating sulfamethoxazoleand trimethoprim.Chronic

Use of BACTRIM at high doses and/or for extended periods of time may cause bonemarrow depression manifested as thrombocytopenia, leukopenia and/or megaloblasticanemia. If signs of bone marrow depression occur, the patient should be givenleucovorin 5 to 15 mg daily until normal hematopoiesis is restored.

DOSAGE AND ADMINISTRATIONBACTRIM is contraindicated in pediatric patients less than 2 months of age.Urinary Tract Infections and Shigellosis in Adults and Pediatric Patients, andAcute Otitis Media in ChildrenAdults: The usual adult dosage in the treatment of urinary tract infections is 1 BACTRIMDS (double strength) tablet or 2 BACTRIM tablets every 12 hours for 10 to 14 days. Anidentical daily dosage is used for 5 days in the treatment of shigellosis.Children: The recommended dose for children with urinary tract infections or acute otitismedia is 40 mg/kg sulfamethoxazole and 8 mg/kg trimethoprim per 24 hours, given intwo divided doses every 12 hours for 10 days. An identical daily dosage is used for 5days in the treatment of shigellosis. The following table is a guideline for the attainmentof this dosage:

Children 2 months of age or older:Weight Dose–every 12 hours

lb kg Tablets22 10 –44 20 166 30 1½88 40 2 or 1 DS tablet

For Patients with Impaired Renal FunctionWhen renal function is impaired, a reduced dosage should be employed using thefollowing table:

Creatinine Clearance (mL/min)

Recommended Dosage Regimen

Above 30 Usual standard regimen15–30 ½ the usual regimen

Below 15 Use not recommended

Acute Exacerbations of Chronic Bronchitis in Adults The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 1BACTRIM DS (double strength) tablet or 2 BACTRIM tablets every 12 hours for 14 days.Pneumocystis jirovecii Pneumonia Treatment

Adults and Children: The recommended dosage for treatment of patients with documented Pneumocystisjirovecii pneumonia is 75 to 100 mg/kg sulfamethoxazole and 15 to 20 mg/kg

trimethoprim per 24 hours given in equally divided doses every 6 hours for 14 to 21days. The following table is a guideline for the upper limit of this dosage:

Weight Dose–every 6 hourslb kg Tablets18 8 –35 16 153 24 1½70 32 2 or 1 DS tablet88 40 2½106 48 3 or 1½ DS tablets141 64 4 or 2 DS tablets176 80 5 or 2½ DS tablets

For the lower limit dose (75 mg/kg sulfamethoxazole and 15 mg/kg trimethoprim per 24hours) administer 75% of the dose in the above table.Prophylaxis Adults:

The recommended dosage for prophylaxis in adults is 1 BACTRIM DS (double strength)tablet daily.Children: For children, the recommended dose is 750 mg/m /day sulfamethoxazole with 150mg/m /day trimethoprim given orally in equally divided doses twice a day, on 3consecutive days per week. The total daily dose should not exceed 1600 mgsulfamethoxazole and 320 mg trimethoprim. The following table is a guideline for theattainment of this dosage in children:

Body Surface Area Dose–every 12 hours(m ) Tablets0.26 –0.53 ½1.06 1

Traveler’s Diarrhea in Adults For the treatment of traveler’s diarrhea, the usual adult dosage is 1 BACTRIM DS (doublestrength) tablet or 2 BACTRIM tablets every 12 hours for 5 days.

HOW SUPPLIEDBACTRIM™ TABLETS are supplied as follows:BACTRIM™ DS (double strength) TABLETS (white, oval shaped, scored) containing 160mg trimethoprim and 800 mg sulfamethoxazole – bottles of 100 (NDC 49708-146-01).Imprint on tablets (debossed): (front) BACTRIM DSBACTRIM™ TABLETS (white, round, scored) containing 80 mg trimethoprim and 400 mgsulfamethoxazole – bottles of 100 (NDC 49708-145-01). Imprint on tablets (debossed):

12

13

22

14

2

(front) BACTRIMStore at 20° to 25°C (68° to 77°F).[See USP Controlled Room Temperature]DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.

REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

All trademarks are property of their respective owners.Distributed by:Sun Pharmaceutical Industries, Inc.Cranbury, NJ 08512Rev. 06, April 2021

Kremers P, Duvivier J, Heusghem C. Pharmacokinetic Studies of Co-Trimoxazole inMan after Single and Repeated Doses. J Clin Pharmacol. Feb-Mar 1974; 14:112–117.Kaplan SA, et al. Pharmacokinetic Profile of Trimethoprim-Sulfamethoxazole in Man.J Infect Dis. Nov 1973; 128 (Suppl): S547–S555.Varoquaux O, et al. Pharmacokinetics of the trimethoprim-sulfamethoxazolecombination in the elderly. Br J Clin Pharmacol. 1985; 20:575–581.Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associatedwith an increased risk of therapeutic failure and death. J Infect Dis. 1994Oct;170(4):912–7.Marinella Mark A. 1999. Trimethoprim-induced hyperkalemia: An analysis ofreported cases. Gerontol. 45:209–212.Margassery, S. and B. Bastani. 2002. Life threatening hyperkalemia and acidosissecondary to trimethoprim-sulfamethoxazole treatment. J. Nephrol. 14:410–414.Moh R, et al. Haematological changes in adults receiving a zidovudine-containingHAART regimen in combination with cotrimoxazole in Côte d’Ivoire. Antivir Ther.2005;10(5):615-24.Al-Khatib SM, LaPointe N, Kramer JM, Califf RM. What Clinicians Should Know Aboutthe QT Interval. JAMA. 2003;289(16):2120-2127.Boyer EW, Stork C, Wang RY. Review: The Pharmacology and Toxicology ofDofetilide. Int J Med Toxicol. 2001;4(2):16.Kosoglou T, Rocci ML Jr, Vlasses PH. Trimethoprim alters the disposition ofprocainamide and N-acetylprocainamide. Clin Pharmacol Ther. Oct 1988;44(4):467-77.Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment ofBacteriuria in Women. J Infect Dis. Nov 1973; 128 (Suppl): S657–S663.Masur H. Prevention and treatment of Pneumocystis pneumonia. N Engl J Med.1992; 327: 1853–1880.Recommendations for prophylaxis against Pneumocystis carinii pneumonia foradults and adolescents infected with human immunodeficiency virus. MMWR. 1992;41(RR–4):1–11.CDC Guidelines for prophylaxis against Pneumocystis carinii pneumonia for childreninfected with human immunodeficiency virus. MMWR. 1991; 40(RR–2):1–13.

PRINCIPAL DISPLAY PANEL - 400 mg/80 mg Tablet Bottle Label

PRINCIPAL DISPLAY PANEL - 800 mg/160 mg Tablet Bottle Label

BACTRIM DS sulfamethoxazole and trimethoprim tablet

Product InformationProduct Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:49708-146

Route of Administration ORAL

Active Ingredient/Active MoietyIngredient Name Basis of

Strength Strength

SULFAMETHOXAZOLE (UNII: JE42381TNV) (SULFAMETHOXAZOLE -UNII:JE42381TNV) SULFAMETHOXAZOLE 800 mg

TRIMETHOPRIM (UNII: AN164J8Y0X) (TRIMETHOPRIM - UNII:AN164J8Y0X) TRIMETHOPRIM 160 mg

Inactive IngredientsIngredient Name Strength

DOCUSATE SODIUM (UNII: F05Q2T2JA0) SODIUM BENZOATE (UNII: OJ245FE5EU) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) MAGNESIUM STEARATE (UNII: 70097M6I30) STARCH, CORN (UNII: O8232NY3SJ)

Product CharacteristicsColor white Score 2 piecesShape OVAL Size 19mmFlavor Imprint Code Bactrim;DSContains

PackagingMarketing Start Marketing End

# Item Code Package Description Marketing StartDate

Marketing EndDate

1 NDC:49708-146-01

100 in 1 BOTTLE, PLASTIC; Type 0: Not aCombination Product 11/01/2004

Marketing InformationMarketingCategory

Application Number or MonographCitation

Marketing StartDate

Marketing EndDate

NDA NDA017377 11/01/2004

BACTRIM sulfamethoxazole and trimethoprim tablet

Product InformationProduct Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:49708-145

Route of Administration ORAL

Active Ingredient/Active MoietyIngredient Name Basis of

Strength Strength

SULFAMETHOXAZOLE (UNII: JE42381TNV) (SULFAMETHOXAZOLE -UNII:JE42381TNV) SULFAMETHOXAZOLE 400 mg

TRIMETHOPRIM (UNII: AN164J8Y0X) (TRIMETHOPRIM - UNII:AN164J8Y0X) TRIMETHOPRIM 80 mg

Inactive IngredientsIngredient Name Strength

DOCUSATE SODIUM (UNII: F05Q2T2JA0) SODIUM BENZOATE (UNII: OJ245FE5EU) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) MAGNESIUM STEARATE (UNII: 70097M6I30) STARCH, CORN (UNII: O8232NY3SJ)

Product CharacteristicsColor white Score 2 piecesShape ROUND Size 11mmFlavor Imprint Code BactrimContains

Packaging# Item Code Package Description Marketing Start

DateMarketing End

Date1 NDC:49708-

145-01100 in 1 BOTTLE, PLASTIC; Type 0: Not aCombination Product 11/01/2004

Sun Pharmaceutical Industries, Inc

Marketing InformationMarketingCategory

Application Number or MonographCitation

Marketing StartDate

Marketing EndDate

NDA NDA017377 11/01/2004

Labeler - Sun Pharmaceutical Industries, Inc (146974886)

EstablishmentName Address ID/FEI Business Operations

Frontida BioPharm, Inc. 080243260 MANUFACTURE(49708-146, 49708-145)

EstablishmentName Address ID/FEI Business Operations

ALKALOIDA 643611692 MANUFACTURE(49708-146, 49708-145)

Revised: 4/2021